WO2001004115A2 - Novel process for synthesis of heteroaryl-substituted urea compounds - Google Patents
Novel process for synthesis of heteroaryl-substituted urea compounds Download PDFInfo
- Publication number
- WO2001004115A2 WO2001004115A2 PCT/US2000/017655 US0017655W WO0104115A2 WO 2001004115 A2 WO2001004115 A2 WO 2001004115A2 US 0017655 W US0017655 W US 0017655W WO 0104115 A2 WO0104115 A2 WO 0104115A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- group
- optionally
- branched
- groups
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 41
- 150000003672 ureas Chemical class 0.000 title abstract description 10
- 230000015572 biosynthetic process Effects 0.000 title description 13
- 238000003786 synthesis reaction Methods 0.000 title description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- 125000000217 alkyl group Chemical group 0.000 claims description 116
- -1 Ci ^alkoxy Chemical group 0.000 claims description 86
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 44
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 43
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 36
- 239000002904 solvent Substances 0.000 claims description 35
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 34
- 125000003545 alkoxy group Chemical group 0.000 claims description 32
- 125000000623 heterocyclic group Chemical group 0.000 claims description 32
- 125000001624 naphthyl group Chemical group 0.000 claims description 30
- 125000005843 halogen group Chemical group 0.000 claims description 27
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 26
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 22
- 229910052736 halogen Inorganic materials 0.000 claims description 21
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 19
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 18
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 16
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 16
- 229910052760 oxygen Inorganic materials 0.000 claims description 16
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 claims description 15
- 125000004043 oxo group Chemical group O=* 0.000 claims description 15
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 14
- 125000004076 pyridyl group Chemical group 0.000 claims description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 13
- SECXISVLQFMRJM-UHFFFAOYSA-N NMP Substances CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 13
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 13
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 229930192474 thiophene Natural products 0.000 claims description 11
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 10
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 10
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 10
- 125000002883 imidazolyl group Chemical group 0.000 claims description 10
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 8
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 8
- 125000003282 alkyl amino group Chemical group 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
- 125000002541 furyl group Chemical group 0.000 claims description 8
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 8
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 8
- 125000005647 linker group Chemical group 0.000 claims description 8
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 8
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 8
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 8
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 8
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 8
- 229920006395 saturated elastomer Polymers 0.000 claims description 8
- 125000001544 thienyl group Chemical group 0.000 claims description 8
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 claims description 7
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- 125000004122 cyclic group Chemical group 0.000 claims description 6
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 claims description 6
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 6
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims description 6
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 6
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 claims description 6
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims description 5
- 125000003435 aroyl group Chemical group 0.000 claims description 5
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 claims description 4
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 claims description 4
- QYCGBAJADAGLLK-UHFFFAOYSA-N 1-(cyclohepten-1-yl)cycloheptene Chemical group C1CCCCC=C1C1=CCCCCC1 QYCGBAJADAGLLK-UHFFFAOYSA-N 0.000 claims description 4
- VSIYJQNFMOOGCU-UHFFFAOYSA-N 1-(cyclohexen-1-yl)cyclohexene Chemical group C1CCCC(C=2CCCCC=2)=C1 VSIYJQNFMOOGCU-UHFFFAOYSA-N 0.000 claims description 4
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 4
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 4
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims description 4
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 4
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 claims description 4
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 4
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 4
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 4
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 4
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 4
- 150000003512 tertiary amines Chemical class 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 3
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 claims description 3
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 3
- 150000008282 halocarbons Chemical class 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- 125000000018 nitroso group Chemical group N(=O)* 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 2
- NQPJDJVGBDHCAD-UHFFFAOYSA-N 1,3-diazinan-2-one Chemical compound OC1=NCCCN1 NQPJDJVGBDHCAD-UHFFFAOYSA-N 0.000 claims description 2
- FLBAYUMRQUHISI-UHFFFAOYSA-N 1,8-naphthyridine Chemical compound N1=CC=CC2=CC=CN=C21 FLBAYUMRQUHISI-UHFFFAOYSA-N 0.000 claims description 2
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 claims description 2
- GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical compound C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 claims description 2
- KMTRUDSVKNLOMY-UHFFFAOYSA-N Ethylene carbonate Chemical compound O=C1OCCO1 KMTRUDSVKNLOMY-UHFFFAOYSA-N 0.000 claims description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical group NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 claims description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 2
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 2
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 2
- YPWFISCTZQNZAU-UHFFFAOYSA-N Thiane Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 claims description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 2
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 claims description 2
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004599 benzpyrazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 claims description 2
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 claims description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N dihydromaleimide Natural products O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 claims description 2
- 125000005046 dihydronaphthyl group Chemical group 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 2
- 125000005844 heterocyclyloxy group Chemical group 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 2
- 125000001041 indolyl group Chemical group 0.000 claims description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 2
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 claims description 2
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 claims description 2
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 claims description 2
- 125000004742 propyloxycarbonyl group Chemical group 0.000 claims description 2
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 claims description 2
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 2
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims description 2
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 2
- 150000003335 secondary amines Chemical class 0.000 claims description 2
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 2
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 claims description 2
- ISXOBTBCNRIIQO-UHFFFAOYSA-N tetrahydrothiophene 1-oxide Chemical compound O=S1CCCC1 ISXOBTBCNRIIQO-UHFFFAOYSA-N 0.000 claims description 2
- 150000003536 tetrazoles Chemical class 0.000 claims description 2
- BUGOPWGPQGYYGR-UHFFFAOYSA-N thiane 1,1-dioxide Chemical compound O=S1(=O)CCCCC1 BUGOPWGPQGYYGR-UHFFFAOYSA-N 0.000 claims description 2
- NNLBRYQGMOYARS-UHFFFAOYSA-N thiane 1-oxide Chemical compound O=S1CCCCC1 NNLBRYQGMOYARS-UHFFFAOYSA-N 0.000 claims description 2
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 claims description 2
- YFHICDDUDORKJB-UHFFFAOYSA-N trimethylene carbonate Chemical compound O=C1OCCCO1 YFHICDDUDORKJB-UHFFFAOYSA-N 0.000 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 239000003586 protic polar solvent Substances 0.000 claims 1
- 230000035484 reaction time Effects 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 9
- 201000010099 disease Diseases 0.000 abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 3
- 206010061218 Inflammation Diseases 0.000 abstract description 2
- 208000037976 chronic inflammation Diseases 0.000 abstract description 2
- 208000037893 chronic inflammatory disorder Diseases 0.000 abstract description 2
- 230000004054 inflammatory process Effects 0.000 abstract description 2
- 230000001575 pathological effect Effects 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 21
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 19
- 239000004202 carbamide Substances 0.000 description 17
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 16
- 235000013877 carbamide Nutrition 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- 235000019439 ethyl acetate Nutrition 0.000 description 13
- 238000001914 filtration Methods 0.000 description 13
- 239000000543 intermediate Substances 0.000 description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 239000012267 brine Substances 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- IXJIGWUIXVMATA-UHFFFAOYSA-N 2,2,2-trichloroethyl n-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamate Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)OCC(Cl)(Cl)Cl)=CC(C(C)(C)C)=N1 IXJIGWUIXVMATA-UHFFFAOYSA-N 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000010410 layer Substances 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 235000011121 sodium hydroxide Nutrition 0.000 description 5
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 4
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000012948 isocyanate Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 150000002513 isocyanates Chemical class 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 description 2
- XUDZVPPOGUXQQS-UHFFFAOYSA-N 2,2,2-trichloroethyl n-(5-tert-butyl-2-methylphenyl)carbamate Chemical compound CC1=CC=C(C(C)(C)C)C=C1NC(=O)OCC(Cl)(Cl)Cl XUDZVPPOGUXQQS-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 0 CC(C)(C)c(cc1*C(Nc(cc2)c(cccc3)c3c2-c2ccc(CN3CCOCC3)nc2)=O)n[n]1-c1ccc(C)cc1 Chemical compound CC(C)(C)c(cc1*C(Nc(cc2)c(cccc3)c3c2-c2ccc(CN3CCOCC3)nc2)=O)n[n]1-c1ccc(C)cc1 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- UCPVBLRLRLJZRP-UHFFFAOYSA-N Nc1ccc(-c2ccc(CN3CCOCC3)nc2)c2ccccc12 Chemical compound Nc1ccc(-c2ccc(CN3CCOCC3)nc2)c2ccccc12 UCPVBLRLRLJZRP-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 125000005241 heteroarylamino group Chemical group 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 2
- 239000011736 potassium bicarbonate Substances 0.000 description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 235000011118 potassium hydroxide Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- ZDCIHNWVXROPMN-UHFFFAOYSA-N (2,4,5-trichlorophenyl) carbonochloridate Chemical compound ClC(=O)OC1=CC(Cl)=C(Cl)C=C1Cl ZDCIHNWVXROPMN-UHFFFAOYSA-N 0.000 description 1
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 1
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 1
- 125000000081 (C5-C8) cycloalkenyl group Chemical group 0.000 description 1
- CXBDYQVECUFKRK-UHFFFAOYSA-N 1-methoxybutane Chemical compound CCCCOC CXBDYQVECUFKRK-UHFFFAOYSA-N 0.000 description 1
- KPWDGTGXUYRARH-UHFFFAOYSA-N 2,2,2-trichloroethanol Chemical compound OCC(Cl)(Cl)Cl KPWDGTGXUYRARH-UHFFFAOYSA-N 0.000 description 1
- MXZMACXOMZKYHJ-UHFFFAOYSA-N 4,4-dimethyl-3-oxopentanenitrile Chemical compound CC(C)(C)C(=O)CC#N MXZMACXOMZKYHJ-UHFFFAOYSA-N 0.000 description 1
- ABJQKDJOYSQVFX-UHFFFAOYSA-N 4-aminonaphthalen-1-ol Chemical compound C1=CC=C2C(N)=CC=C(O)C2=C1 ABJQKDJOYSQVFX-UHFFFAOYSA-N 0.000 description 1
- AUIRNGLMBHIITH-UHFFFAOYSA-N 4-nitronaphthalen-1-ol Chemical compound C1=CC=C2C(O)=CC=C([N+]([O-])=O)C2=C1 AUIRNGLMBHIITH-UHFFFAOYSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- IKJJFZMMHAIPNB-UHFFFAOYSA-N CC(C)(C)c(cc1NC(Nc(cc2)c(cccc3)c3c2-c2ccc(CN3CCOCC3)[o]2)=O)n[n]1-c1ccc(C)cc1 Chemical compound CC(C)(C)c(cc1NC(Nc(cc2)c(cccc3)c3c2-c2ccc(CN3CCOCC3)[o]2)=O)n[n]1-c1ccc(C)cc1 IKJJFZMMHAIPNB-UHFFFAOYSA-N 0.000 description 1
- DVBKZPSCTGHZHB-UHFFFAOYSA-N CC(C)(C)c1cc(NC(Nc2ccc(-c3ccc(CN4CCOCC4)nc3)c3ccccc23)=O)c(C)cc1 Chemical compound CC(C)(C)c1cc(NC(Nc2ccc(-c3ccc(CN4CCOCC4)nc3)c3ccccc23)=O)c(C)cc1 DVBKZPSCTGHZHB-UHFFFAOYSA-N 0.000 description 1
- RHMUKBJFLCQVMF-UHFFFAOYSA-N CN(CCCOC)c(nc1)ccc1-c(c1ccccc11)ccc1N Chemical compound CN(CCCOC)c(nc1)ccc1-c(c1ccccc11)ccc1N RHMUKBJFLCQVMF-UHFFFAOYSA-N 0.000 description 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- IJLMFMVGZPXOAN-UHFFFAOYSA-N Nc(cc1)c(cccc2)c2c1-c1ccc(CN2CCOCC2)[o]1 Chemical compound Nc(cc1)c(cccc2)c2c1-c1ccc(CN2CCOCC2)[o]1 IJLMFMVGZPXOAN-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- ZXYBIPTYOWWVQD-UHFFFAOYSA-N bis(benzotriazol-1-yl)methanone Chemical compound N1=NC2=CC=CC=C2N1C(=O)N1C2=CC=CC=C2N=N1 ZXYBIPTYOWWVQD-UHFFFAOYSA-N 0.000 description 1
- KFDKSWDECHPONU-UHFFFAOYSA-N bis(trichloromethyl) carbonate Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl.ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl KFDKSWDECHPONU-UHFFFAOYSA-N 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical class OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 1
- JYWJULGYGOLCGW-UHFFFAOYSA-N chloromethyl chloroformate Chemical compound ClCOC(Cl)=O JYWJULGYGOLCGW-UHFFFAOYSA-N 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000016396 cytokine production Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- DMDOTRUOIVBPSF-UHFFFAOYSA-N naphthalene;hydrochloride Chemical compound Cl.C1=CC=CC2=CC=CC=C21 DMDOTRUOIVBPSF-UHFFFAOYSA-N 0.000 description 1
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 125000005184 naphthylamino group Chemical group C1(=CC=CC2=CC=CC=C12)N* 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- JIBAEWYZMHBYND-UHFFFAOYSA-N o-(2,2,2-trichloroethyl) chloromethanethioate Chemical compound ClC(=S)OCC(Cl)(Cl)Cl JIBAEWYZMHBYND-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- MKIFFISYTYREEU-UHFFFAOYSA-N phenyl 2h-tetrazole-5-carboxylate Chemical compound N=1N=NNC=1C(=O)OC1=CC=CC=C1 MKIFFISYTYREEU-UHFFFAOYSA-N 0.000 description 1
- BSCCSDNZEIHXOK-UHFFFAOYSA-N phenyl carbamate Chemical compound NC(=O)OC1=CC=CC=C1 BSCCSDNZEIHXOK-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/38—Nitrogen atoms
- C07D231/40—Acylated on said nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- This invention relates to novel processes for preparing new aryl-and heteroaryl- substituted urea compounds of formula (I):
- Arj, Ar 2 , X, L and Q are defined below, which are useful for treating diseases and pathological conditions involving inflammation such as chronic inflammatory disease.
- Aryl- and heteroaryl-substituted ureas have been described as inhibitors of cytokine production. Examples of such compounds are reported in WO 99/23091 and in WO 98/52558. These inhibitors are described as effective therapeutics in cytokine-mediated diseases, including inflammatory and autoimmune diseases.
- the isocyanate III may be prepared by reaction of an aryl or heteroaryl amine Ar 2 NH 2 with phosgene or a phosgene equivalent, such as bis(trichloromethyl) carbonate (triphosgene) (P. Majer and R. S. Randad, J. Org. Chem. 1994, 59, 1937) or trichloromethyl chloroformate (diphosgene). K. Kurita, T. Matsumura and Y. Iwakura, J. Org. Chem. 1976, 41, 2070) to form the isocyanate III, followed by reaction with Ar ⁇ NH 2 to provide the urea.
- phosgene or a phosgene equivalent such as bis(trichloromethyl) carbonate (triphosgene) (P. Majer and R. S. Randad, J. Org. Chem. 1994, 59, 1937) or trichloromethyl chloroformate (diphosgene). K. Kurita, T. Matsumura
- phosgene and phosgene equivalents are hazardous and dangerous to use, particularly in large-scale applications.
- isocyanate intermediate III is not stable and may undergo decomposition during preparation and storage.
- the urea formation may be done using a phenyl carbamate, as illustrated in Scheme II and U.S. Application Serial No. 09/484,638.
- the by-product phenol formed in the urea synthesis does not have sufficient water solubility to be easily removed by water washing especially at large scale. Thus it may require multiple washing and several crystallizations to obtain highly pure product. For these reasons these methods are not well-suited for industrial-scale production.
- U.S. Application Serial No. 09/484,638 also discloses the synthesis of substituted naphthyl amino intermediates for use in making aryl-and heteroaryl-substituted urea compounds of the formula(I) as described therein.
- This synthesis begins with 4- aminonapthol which is protected with a Boc (te -butoxycarbonyl) group on the amine prior to alkylation and deprotection.
- Boc te -butoxycarbonyl
- This procedure is also not amenable to industrial- scale production.
- the starting 4-aminonaphthol is very expensive and not available in large quantity. In addition the protection and deprotection steps are tedious and add to the expense.
- this invention provides efficient methods for preparing intermediates used in the preparation of preferred cytokine-inhibiting aryl-and heteroaryl-substituted ureas. These processes are especially well-suited for preparation of these compounds on an industrial scale.
- the present invention is directed to the synthesis of compounds having formula
- Ari is a heterocyclic group selected from the group consisting of phenyl, pyridine, pyridone, pyrrole, pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan and thiophene; wherein Ari is optionally substituted by one or more R l s R or R 3 ;
- Ar 2 is:
- L a linking group
- Ci-io saturated or unsaturated branched or unbranched carbon chain wherein one or more methylene groups are optionally independently replaced by O,N or S; and wherein said linking group is optionally substituted with 0-2 oxo groups and one or more C M branched or unbranched alkyl optionally substituted by one or more halogen atoms; or L is a cyclic group which is: a) a Cs-s cycloalkyl or cycloalkenyl optionally substituted with 1-2 oxo groups, 1-3 C ⁇ branched or unbranched alkyl, C alkoxy or C alkylamino chains; b) phenyl, furan, thiophene, pyrrole, imidazolyl, pyridine, pyrimidine, pyridinone, dihydropyridinone, maleimide, dihydromaleimide, piperdine, piperazine or pyrazine each being optional
- Q is selected from the group consisting of:
- Ri is selected from the group consisting of:
- C 5- cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one to three C ⁇ -3 alkyl groups;
- R 2 is selected from the group consisting of:
- a C ⁇ -6 branched or unbranched alkyl optionally partially or fully halogenated, acetyl, aroyl, C ⁇ -4 branched or unbranched alkoxy optionally partially or fully halogenated, halogen, methoxycarbonyl and phenylsulfonyl;
- R 3 is selected from the group consisting of:
- heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described, NH 2 C(O), a mono- or di-(C ⁇ -3 )alkyl aminocarbonyl, C ⁇ - alkyl-C(O)-CM alkyl, amino-C ⁇ - 5 alkyl, mono- or di-(C ⁇ . 3 )alkylamino-C ⁇ -5 alkyl, amino-S(O) 2 , di-(C ⁇ -3 )alkylamino-S(O) 2 , R 4 -C ⁇ -5 alkyl, R 5 -C 1 .
- a fused aryl selected from the group consisting of benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heterocyclyl selected from cyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinoline, cyclohexanoquinoline, cyclopentanoisoquinoline, cyclohexanoisoquinoline, cyclohexanoiso
- cycloalkyl selected from the group consisting of cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, wherein the cycloalkyl is optionally partially or fully halogenated and optionally substituted with one to three C ⁇ -3 alkyl groups;
- C 5- cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one to three C ⁇ -3 alkyl groups;
- Ri and R 2 taken together optionally form a fused phenyl or pyridinyl ring;
- each R 8 or R ⁇ 3 is independently selected from the group consisting of:
- each R 4 , R , R ⁇ , R 7 , R 9 , R ⁇ 0 , Rn and R ⁇ 2 is independently selected from the group consisting of: morpholine, piperidine, piperazine, imidazole and tetrazole; m is 0, 1 or 2;
- q 0, 1 or 2;
- r 0, 1 or 2;
- t 0, 1 or 2;
- X is O or S.
- the compounds of the invention may be prepared as physiologically and pharmaceutically acceptable salts, as may seem appropriate to one of ordinary skill in the art.
- the compounds produced by the novel process of the invention are only those which are contemplated to be 'chemically stable' as will be appreciated by those skilled in the art.
- a compound which would have a 'dangling valency', or a 'carbanion' are not compounds contemplated to be made by the novel process.
- Ci ⁇ alkoxy is a C M alkyl with a terminal oxygen, such as methoxy, ethoxy, propoxy, pentoxy and hexoxy.
- All alkyl, alkenyl and alkynyl groups shall be understood as being branched or unbranched where structurally possible and unless otherwise specified. Other more specific definitions are as follows:
- aroyl as used in the present specification shall be understood to mean “benzoyl” or "naphthoyl”.
- NMP l-methyl-2-pyrrolidinone
- THF tetrahydrofuran
- DMF N,N'-dimethylformamide
- DMAC N-N'-dimethylacetamide
- DMSO dimethylsulfoxide
- DMAP 4-dimethylaminopyridine
- DBU l,8-diazabicyclo[5.4.0]undec-7-ene;
- PROCESS FOR MAKING COMPOUNDS OF THE FORMU A The novel process comprises: STEP 1:
- RaOC(X)Ha are those, which upon hydrolysis of the formula(II) intermediates, will form a water soluble byproduct which is easily removed by aqueous washing, such byproduct would be, for example, 2,2,2-trichloroethanol.
- Examples of preferred RaOCOHa are trichloroethyl chloroformate or trichloroethyl chlorothioformate. Accordingly, a preferred compound of the formula(II) is:
- reaction conditions such as the selection of a suitable solvent and temperature is within the skill of the ordinary artisan depending on the particular compounds desired.
- the reaction of step 1 is in a non-aqueous or an aqueous solvent, preferably THF or ethyl acetate, in the presence of a suitable base such as tertiary amine for example triethylamine, diisopropylethylamine, N-methylpyrrolidine, DBU(1,8- diazabicyclo[5.4.0]undec-7-ene), DMAP(4-dimethylaminopyridine), N- methylmorpholine, pyridine, methyl pyridine or inorganic bases such as sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate and potassium bicarbonate.
- a suitable base such as tertiary amine for example triethylamine, diisopropylethylamine, N-methylpyrrolidine, DBU(1,8- diazabicyclo[
- Preferred suitable bases for step 1 are diisopropylethylamine, NaOH or N-methylpyrrolidine.
- the reaction occurs at a temperature of about 0 - 100°C, preferably 5 - 15 °C, for about 0.5 - 24 hrs, preferably 3- 4 hrs.
- Step 2 proceeds as follows. Reacting a Z-Ar 2 -MH, where Z is a nitro or nitroso group, M is O, S, or NH, and Ar 2 is as defined hereinabove, with a Y-J-Q moiety in a suitable solvent to produce the intermediate of formula (III)
- Y is a leaving group such as a halogen and M-J constitutes L;
- a suitable solvent for the above reaction would be a polar non-protic organic solvent, such as acetonitrile, DMF (N,N'-dimethylformamide), DMAC (N-N'- dimethylacetamide), DMSO (dimethylsulfoxide) and NMP (l-methyl-2-pyrrolidinone), preferably NMP, at a temperature of about 50 - 100 °C, preferably between 75 - 95 °C, for about 0.5-24 hrs, preferably 3-4 hrs.
- Catalytic hydrogenation is preferred, a preferred catalyst is Pd C.
- Reaction conditions such as the selection of a suitable solvent and temperature is within the skill of the ordinary artisan.
- the catalytic hydrogenation with respect to H 2 pressure and time can be varied, a preferable hydrogenation occurs under about 30 psi for about 1 hr - 24 hours.
- a suitable base will be one such as tertiary amine for example triethylamine, diisopropylethylamine, N-methylpyrrolidine, DBU, DMAP, N-methylmorpholine, pyridine, methyl pyridine or an inorganic base such as sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate and potassium bicarbonate.
- Preferred bases are diisopropylethylamine or N- methylpyrrolidine.
- Reaction conditions such as the selection of a suitable solvent, base and temperature can be varied according to the specific compound of the formula(I) that is desired.
- the reaction can be run in a suitable polar, or a suitable non-polar solvent such as methylene chloride or chloroform or in heptane, hexane, cyclohexane, ethyl acetate, benzene, toluene, xylene, tetrahydropfuran, dioxane, ethyl ether, methyl butyl ether or in a biphasic aqueous/organic mixture.
- a suitable polar, or a suitable non-polar solvent such as methylene chloride or chloroform or in heptane, hexane, cyclohexane, ethyl acetate, benzene, toluene, xylene, tetrahydropfuran, dioxane, e
- the solvent will be a polar non-protic organic solvent such as NMP(l-methyl-2-pyrrolidinone), acetonitrile, DMF(N,N-dimethylformamide), DMAC(N,N-dimethylacetamide) or DMSO, more preferably DMSO or NMP, which is heated to an appropriate temperature, preferably about 55-60 °C for about 1.5 hours.
- a polar non-protic organic solvent such as NMP(l-methyl-2-pyrrolidinone), acetonitrile, DMF(N,N-dimethylformamide), DMAC(N,N-dimethylacetamide) or DMSO, more preferably DMSO or NMP, which is heated to an appropriate temperature, preferably about 55-60 °C for about 1.5 hours.
- a preferred subgeneric aspect of the invention comprises a process of producing compounds of the formula(I) wherein Ar 2 is naphthyl, tetrahydronaphthyl, indanyl or indenyl.
- a more preferred subgeneric aspect of the invention comprises a process of producing compounds of the formula(I) wherein Ar 2 is naphthyl.
- a yet more preferred subgeneric aspect of the invention comprises a process of producing compounds of the formula (I), as described in the immediate previous paragraph, wherein: Ari is thiophene or pyrazole; Ar 2 is 1 -naphthyl;
- L is C ⁇ -6 saturated or unsaturated branched or unbranched carbon chain wherein one or more methylene groups are optionally independently replaced by O,N or S; and wherein said linking group is optionally substituted with 0-2 oxo groups and one or more CM branched or unbranched alkyl optionally substituted by one or more halogen atoms; or L is cyclopentenyl, cyclohexenyl, cycloheptenyl, each optionally substituted with an oxo group or 1-3 C M branched or unbranched alkyl, CMalkoxy or C M alkylamino; or L is phenyl, pyridine, furan or thiophene each being optionally independently substituted with 1-3 C M branched or unbranched alkyl, d -4 alkoxy, hydroxy, cyano, mono- or di- (C ⁇ -3 alkyl)amino, C ⁇ -6 alkyl-S(O) q or
- Ri is C 3-4 alkyl branched or unbranched, cyclopropyl or cyclohexanyl optionally partially or fully halogenated and optionally substituted with one to three C ⁇ -3 alkyl groups;
- R 3 is selected from the group consisting of C M alkyl branched or unbranched optionally partially or fully halogenated, cyclopentanyl optionally partially or fully halogenated and optionally substituted with one to three C ⁇ -3 alkyl groups, phenyl, pyridinyl each being optionally substituted with one to five groups selected from the group consisting of a C ⁇ -6 branched or unbranched alkyl, phenyl, naphthyl, pyridinyl, C ⁇ -6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C ⁇ -5 alkyl, naphthyl C ⁇ -5 alkyl, halo, hydroxy, cyano, C ⁇ -3
- a yet further preferred subgeneric aspect of the invention comprises a process of producing compounds of the formula (I), as described in the immediate previous paragraph, wherein Ari is pyrazole.
- a still yet further preferred subgeneric aspect of the invention comprises a process of producing compounds of the formula (I), as described in the immediate previous paragraph, wherein L is C ⁇ -5 saturated carbon chain wherein one or more methylene groups are optionally independently replaced by O,N or S; and wherein said linking group is optionally substituted with 0-2 oxo groups and one or more C M branched or unbranched alkyl optionally substituted by one or more halogen atoms;
- More particularly preferred embodiments of the process of the invention is where L is propoxy, ethoxy, methoxy, methyl, propyl, C 3-5 acetylene or methylamino each being optionally substituted as described herein and Q is morpholine.
- L is ethoxy optionally substituted
- the base is diisopropylethylamine
- the polar non-protic organic solvent is DMSO.
- 5-Amino-3- ⁇ '-butyl-l-p-tolylpyrazole hydrochlonde A solution of pivaloylacetonitrile (750 g, 6.0 mol) and ?-tolylhydrazine hydrochloride (660 g, 4.2 mol) in methanol (2.8 L) was refluxed for 3 h. Heptane was added, and methanol was removed by distillation. The product was crystallized from the solution, collected by filtration and dried in vacuum oven to constant weight. Yield: 1.05 kg, 94%.
- 4-Nitro-l-(2-morpholinethoxy)naphthalene A mixture of 4-nitro-l- hydroxynaphthalene (194 g, 1.0 mol), 4-(2-chloroethyl)mo ⁇ holine hydrochloride (264 g, 1.4 mol), NaOH (58 g, 1.4 mol), K 2 CO 3 (339 g, 2.4 mol) and l-methyl-2-pyrrolidinone (1.0 L) was heated to 90 - 100 °C and held for 1 - 2 h. The mixture was cooled to 40 °C and water was slowly added. The mixture was cooled to 5 °C and held for 4 h.
- 4-Amino-l-(2-morpholinethoxy)naphthalene hydrochloride A mixture of 4-nitro-l- (2-morpholinethoxy)naphthalene (40 g, 0.13 mol), MeOH (280 mL) and Pd/C (50% water, 1.2 g) was hydrogenated under 30 psi for 24 h. The catalyst was filtered through a layer of diatomaceous earth under nitrogen. To this filtrate 20 mL of HCl (37%) and cyclohexane (200 mL) were added. The solvent was removed under reduced pressure and the product collected by filtration. The product was dried in vacuum to constant weight. Yield: 33 g, 82%.
- the solvent is removed under reduced pressure, and residue is crystallized from a suitable solvent such as acetonitrile (50 mL) at 0 °C.
- a suitable solvent such as acetonitrile (50 mL) at 0 °C.
- the product is collected by filtration and recrystallized from a suitable solvent such as isopropanol and dried in vacuum to constant weight.
- the solvent is removed under reduced pressure, and residue is crystallized from a suitable solvent such as acetonitrile (50 mL) at 0 °C.
- a suitable solvent such as acetonitrile (50 mL) at 0 °C.
- the product is collected by filtration and recrystallized from a suitable solvent such as isopropanol and dried in vacuum to constant weight.
- the solvent is removed under reduced pressure, and residue is crystallized from a suitable solvent such as acetonitrile (50 mL) at 0 °C.
- a suitable solvent such as acetonitrile (50 mL) at 0 °C.
- the product is collected by filtration and recrystallized from a suitable solvent such as isopropanol and dried in vacuum to constant weight.
- the solvent is removed under reduced pressure, and residue is crystallized from a suitable solvent such as acetonitrile (50 mL) at 0 °C.
- a suitable solvent such as acetonitrile (50 mL) at 0 °C.
- the product is collected by filtration and recrystallized from a suitable solvent such as isopropanol and dried in vacuum to constant weight.
- the solvent is removed under reduced pressure, and residue is crystallized from a suitable solvent such as acetonitrile (50 mL) at 0 °C.
- a suitable solvent such as acetonitrile (50 mL) at 0 °C.
- the product is collected by filtration and recrystallized from a suitable solvent such as isopropanol and dried in vacuum to constant weight.
- the solvent is removed under reduced pressure, and residue is crystallized from a suitable solvent such as acetonitrile (50 mL) at 0 °C.
- a suitable solvent such as acetonitrile (50 mL) at 0 °C.
- the product is collected by filtration and recrystallized from a suitable solvent such as isopropanol and dried in vacuum to constant weight.
- the solvent is removed under reduced pressure, and residue is crystallized from a suitable solvent such as acetonitrile (50 mL) at 0 °C.
- a suitable solvent such as acetonitrile (50 mL) at 0 °C.
- the product is collected by filtration and recrystallized from a suitable solvent such as isopropanol and dried in vacuum to constant weight.
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Abstract
Disclosed are novel processes and novel intermediate compounds for preparing aryl- and heteroaryl-substituted urea compounds of formula (I) wherein Ar1, Ar2, L, Q and X are described herein. The product compounds are useful in pharmaceutic compositions for treating diseases or pathological conditions involving inflammation such as chronic inflammatory diseases.
Description
Novel Process for Synthesis of Heteroaryl-substituted Urea Compounds
RELATED APPLICATION DATA
This application claims benefit to US Provisional Application Serial No. 60/143,094, filed July 9, 1999.
TECHNICAL FIELD OF THE INVENTION
This invention relates to novel processes for preparing new aryl-and heteroaryl- substituted urea compounds of formula (I):
(I)
wherein Arj, Ar2, X, L and Q are defined below, which are useful for treating diseases and pathological conditions involving inflammation such as chronic inflammatory disease.
BACKGROUND OF THE INVENTION
Aryl- and heteroaryl-substituted ureas have been described as inhibitors of cytokine production. Examples of such compounds are reported in WO 99/23091 and in WO 98/52558. These inhibitors are described as effective therapeutics in cytokine-mediated diseases, including inflammatory and autoimmune diseases.
A key step in the synthesis of these compounds is the formation of the urea bond. Various methods have been reported to accomplish this. For example, as reported in the
above references, an aromatic or heteroaromatic amine, II, may be reacted with an aromatic or heteroaromatic isocyanate III to generate the urea IV (Scheme I)
Scheme I
III IV
If not commercially available, one may prepare the isocyanate III by reaction of an aryl or heteroaryl amine Ar2NH2 with phosgene or a phosgene equivalent, such as bis(trichloromethyl) carbonate (triphosgene) (P. Majer and R. S. Randad, J. Org. Chem. 1994, 59, 1937) or trichloromethyl chloroformate (diphosgene). K. Kurita, T. Matsumura and Y. Iwakura, J. Org. Chem. 1976, 41, 2070) to form the isocyanate III, followed by reaction with ArιNH2 to provide the urea. Other approaches to forming the urea known in the chemical literature are to form a carbamate, as shown in Scheme II below, by reaction of an amine with a chloroformate derivative, such as phenyl chloroformate (B. Thavonekham, Synthesis, 1997, 1189), chloromethyl chloroformate (T. Patonay, E. Patonay-Peli, L Zolnai and F. Mogyorodi, Synthetic Communications, 1996, 26, 4253), p-nitrophenyl chloroformate (J. Gante, Chem. Ber. 1965, 98, 3334), or 2,4,5- trichlorophenyl chloroformate (A. W. Lipkowski, S. W. Tarn and P. S. Portoghese, J. Med. Chem. 1986, 29, 1222) to form a carbamate V. This may then be reacted with an aryl or heteroaryl amine (II) to provide urea IV (Scheme II- reaction with phenyl chloroformate shown). The synthesis of ureas through (phenoxycarbonyl)tetrazole (R. W. Adamiak, J. Stawinski, Tetrahedron Lett. 1977, 1935) or 1,1 '- carbonylbisbenzotriazole (A. R. Katritzky, D. P. M. Pleynet and B. Yang, J. Org. Chem. 1997, 62, 4155) has been reported. In addition, preparation of ureas by catalytic carbonation of amines with carbon monoxide or carbon dioxide has been documented in the literature (N. Sonoda, T. Yasuhara, K. Kondo, T. Ikeda and S. Tsutsumi, J. Am. Chem. Soc. 1971, 93, 691; Y. Morimoto, Y. Fujiwara, H. Taniguchi, Y. Hori and Y.
Nagano, Tetrahedron Lett. 1986, 27, 1809). In each of these cases, Ari and Ar2 may be modified before and/or after the urea formation to produce desired compounds.
Scheme II
V IV
Each of the methods described above suffer from one or more disadvantages. For example, phosgene and phosgene equivalents are hazardous and dangerous to use, particularly in large-scale applications. In addition the isocyanate intermediate III is not stable and may undergo decomposition during preparation and storage. The urea formation may be done using a phenyl carbamate, as illustrated in Scheme II and U.S. Application Serial No. 09/484,638. However, the by-product phenol formed in the urea synthesis does not have sufficient water solubility to be easily removed by water washing especially at large scale. Thus it may require multiple washing and several crystallizations to obtain highly pure product. For these reasons these methods are not well-suited for industrial-scale production.
U.S. Application Serial No. 09/484,638 also discloses the synthesis of substituted naphthyl amino intermediates for use in making aryl-and heteroaryl-substituted urea compounds of the formula(I) as described therein. This synthesis begins with 4- aminonapthol which is protected with a Boc (te -butoxycarbonyl) group on the amine
prior to alkylation and deprotection. This procedure is also not amenable to industrial- scale production. The starting 4-aminonaphthol is very expensive and not available in large quantity. In addition the protection and deprotection steps are tedious and add to the expense.
Disclosed herein are novel processes for making the aryl-and heteroaryl-substituted urea compounds of the formula(I) including those disclosed in U.S. Application Serial No. 09/484,638 and novel intermediates useful in such processes.
BRIEF SUMMARY OF THE INVENTION
It is therefore an object of this invention to provide a general and cost-effective process for the preparation of the aryl- and heteroaryl-substituted urea compounds of the formula(I) shown below:
(I) comprising the steps of: reacting of intermediate of formula (II) with intermediate of formula (IV) to produce the product compound of formula (I):
(II) (IV) (I)
wherein Ari, Ar2, L, Q, X and Ra are as described below.
In addition, this invention provides efficient methods for preparing intermediates used in the preparation of preferred cytokine-inhibiting aryl-and heteroaryl-substituted ureas. These processes are especially well-suited for preparation of these compounds on an industrial scale.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to the synthesis of compounds having formula
(I):
X
Ar^N^N-Ar ~L ■ Q
H H (I) wherein:
Ari is a heterocyclic group selected from the group consisting of phenyl, pyridine, pyridone, pyrrole, pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan and thiophene; wherein Ari is optionally substituted by one or more Rl s R or R3;
Ar2 is:
phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl or indole each being optionally substituted with one to three R2 groups;
L, a linking group, is: Ci-io saturated or unsaturated branched or unbranched carbon chain; wherein one or more methylene groups are optionally independently replaced by O,N or S; and
wherein said linking group is optionally substituted with 0-2 oxo groups and one or more CM branched or unbranched alkyl optionally substituted by one or more halogen atoms; or L is a cyclic group which is: a) a Cs-s cycloalkyl or cycloalkenyl optionally substituted with 1-2 oxo groups, 1-3 Cμ branched or unbranched alkyl, C alkoxy or C alkylamino chains; b) phenyl, furan, thiophene, pyrrole, imidazolyl, pyridine, pyrimidine, pyridinone, dihydropyridinone, maleimide, dihydromaleimide, piperdine, piperazine or pyrazine each being optionally independently substituted with 1-3 CM branched or unbranched alkyl, Cι-4alkoxy, hydroxy, cyano, mono- or di-(Cι-3 alkyl)amino, Cι-6 alkyl-S(O)q, or halogen; wherein said cyclic group is optionally attached to a CM saturated or unsaturated branched or unbranched carbon chain wherein said carbon chain is in turn covalently attached to Q , said carbon chain is optionally partially or fully halogenated and wherein one or more methylene groups are optionally replaced by O, NH, S(O), S(O)2 or S, wherein said methylene groups are further optionally independently substituted with 1-2 oxo groups and one or more C branched or unbranched alkyl optionally substituted by one or more halogen atoms;
Q is selected from the group consisting of:
a) phenyl, naphthyl, pyridine, pyrimidine, pyridazine, imidazole, benzimidazole, furan, thiophene, pyran, naphthyridine, oxazo[4,5-b]pyridine and imidazo[4,5-b]pyridine, which are optionally substituted with one to three groups selected from the group consisting of halogen, Cι-6 alkyl, Cι-6 alkoxy, hydroxy, mono- or di-(Cι-3 alkyl)amino,
Cι-6 alkyl-S(O)m and phenylamino wherein the phenyl ring is optionally substituted with one to two groups selected from the group consisting of halogen, Cι-6 alkyl and Cι-6 alkoxy; b) tetrahydropyran, tetrahydrofuran, 1,3-dioxolanone, 1,3-dioxanone, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine sulfoxide, thiomorpholine sulfone, piperidine, piperidinone, tetrahydropyrimidone, cyclohexanone, cyclohexanol,
pentamethylene sulfide, pentamethylene sulfoxide, pentamethylene sulfone, tetramethylene sulfide, tetramethylene sulfoxide and tetramethylene sulfone which are optionally substituted with one to three groups selected from the group consisting of Cι-6 alkyl, Cι-6 alkoxy, hydroxy, mono- or di-(Cι-3 alkyl)amino-Cι-3 alkyl, phenylamino-Cι-3 alkyl and Cι-3 alkoxy-Cι-3 alkyl; c) Ci-6 alkoxy, secondary or tertiary amine wherein the amino nitrogen is covalently bonded to groups selected from the group consisting of Cι-3 alkyl and Cι-5 alkoxyalkyl and phenyl wherein the phenyl ring is optionally substituted with one to two groups selected from the group consisting of halogen, Cι-6 alkoxy, hydroxy or mono- or di- (Cι-3 alkyl)amino, Cι-6 alkyl-S(O)r and phenyl-S(O)t, wherein the phenyl ring is optionally substituted with one to two groups consisting of halogen, Cι-6 alkoxy, hydroxy and mono- or di-(Cι-3 alkyl)amino;
Ri is selected from the group consisting of:
(a) C3-i0 branched or unbranched alkyl, which may optionally be partially or fully halogenated, and optionally substituted with one to three phenyl, naphthyl or heterocyclic groups selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl; each such phenyl, naphthyl or heterocycle selected from the group hereinabove described, being substituted with 0 to 5 groups selected from the group consisting of halogen, Cι-6 branched or unbranched alkyl which is optionally partially or fully halogenated, C3-8 cycloalkyl, C5-8 cycloalkenyl, hydroxy, cyano, Cι-3 alkyloxy which is optionally partially or fully halogenated, NH2C(O) and di(Cι-3)alkylaminocarbonyl;
(b) C3-7 cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, which are optionally partially or fully halogenated and optionally substituted with one to three Cι-3 alkyl groups, or an analog of such cycloalkyl group wherein one to three ring methylene groups are replaced by groups independently selected from O, S, CHOH, >C=O, >C=S and NH;
(c) C3-ιo branched alkenyl optionally partially or fully halogenated, and optionally substituted with one to three Cι-5 branched or unbranched alkyl, phenyl, naphthyl or heterocyclic groups, with each such heterocyclic group being independently selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, and each such phenyl, naphthyl or heterocyclic group being substituted with 0 to 5 groups selected from halogen, Cι-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, hydroxy, cyano, Cι-3 alkyloxy which is optionally partially or fully halogenated, NH2C(O) and mono- or di(Cι.
3)alkylaminocarbonyl;
(d) C5- cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one to three Cι-3 alkyl groups;
(e) cyano; and,
(f) methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl;
R2 is selected from the group consisting of:
a Cι-6 branched or unbranched alkyl optionally partially or fully halogenated, acetyl, aroyl, Cι-4 branched or unbranched alkoxy optionally partially or fully halogenated, halogen, methoxycarbonyl and phenylsulfonyl;
R3 is selected from the group consisting of:
a) a phenyl, naphthyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl,
benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl and indazolyl wherein such phenyl, naphthyl or heterocyclic group is optionally substituted with one to five groups selected from the group consisting of a Cι-6 branched or unbranched alkyl, phenyl, naphthyl, heterocycle selected from the group hereinabove described, Cι-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl Cι-5 alkyl, naphthyl Cι-5 alkyl, halo, hydroxy, cyano, Cι-3 alkyloxy which may optionally be partially or fully halogenated, phenyloxy, naphthyloxy, heteraryloxy wherein the heterocyclic moiety is selected from the group hereinabove described, nitro, amino, mono- or di-(C].3)alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described, NH2C(O), a mono- or di-(Cι-3)alkyl aminocarbonyl, Cι- alkyl-C(O)-CM alkyl, amino-Cι-5 alkyl, mono- or di-(Cι. 3)alkylamino-Cι-5 alkyl, amino-S(O)2, di-(Cι-3)alkylamino-S(O)2, R4-Cι-5 alkyl, R5-C1.
5 alkoxy, R6-C(O)-Cι-5 alkyl and R7-Cι-5 alkyl-N(R8)-; a fused aryl selected from the group consisting of benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heterocyclyl selected from cyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinoline, cyclohexanoquinoline, cyclopentanoisoquinoline, cyclohexanoisoquinoline, cyclopentanoindole, cyclohexanoindole, cyclopentanobenzimidazole, cyclohexanobenzimidazole, cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; wherein the fused aryl or fused heterocyclyl ring is substituted with 0 to 3 groups independently selected from phenyl, naphthyl, heterocyclyl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, and isothiazolyl, Cι-6 branched or unbranched alkyl which is optionally partially or fully halogenated, halo, cyano, Cι-3 alkyloxy
which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy wherein the heterocyclyl moiety is selected from the group hereinabove described, nitro, amino, mono- or di-(Cι-3)alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described, NH2C(O), a mono- or di-(Cι-3)alkyl aminocarbonyl,
CM alkyl-OC(O), Cι-5 alkyl-C(O)-Cι- branched or unbranched alkyl, an amino-Cι-5 alkyl, mono- or di-(Cι-3)alkylamino-Cι.5 alkyl, Rc>-Cι- alkyl, Rιo-Cι-5 alkoxy, Rπ- C(O)-Ci-5 alkyl and R12-Cι.5 alkyl-N(R13)-; c) cycloalkyl selected from the group consisting of cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, wherein the cycloalkyl is optionally partially or fully halogenated and optionally substituted with one to three Cι-3 alkyl groups;
d) C5- cycloalkenyl, selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one to three Cι-3 alkyl groups;
e) acetyl, aroyl, alkoxycarbonylalkyl and phenylsulfonyl; and
f) d-6 branched or unbranched alkyl optionally partially or fully halogenated;
Ri and R2 taken together optionally form a fused phenyl or pyridinyl ring;
each R8 or Rι3 is independently selected from the group consisting of:
hydrogen and CM branched or unbranched alkyl optionally partially or fully halogenated;
each R4, R , Rό, R7, R9, Rι0, Rn and Rι2 is independently selected from the group consisting of: morpholine, piperidine, piperazine, imidazole and tetrazole;
m is 0, 1 or 2;
q is 0, 1 or 2;
r is 0, 1 or 2;
t is 0, 1 or 2; and
X is O or S.
The compounds of the invention may be prepared as physiologically and pharmaceutically acceptable salts, as may seem appropriate to one of ordinary skill in the art.
The compounds produced by the novel process of the invention are only those which are contemplated to be 'chemically stable' as will be appreciated by those skilled in the art. For example, a compound which would have a 'dangling valency', or a 'carbanion' are not compounds contemplated to be made by the novel process.
All terms as used herein in this specification, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. For example, "Ci ^alkoxy" is a CMalkyl with a terminal oxygen, such as methoxy, ethoxy, propoxy, pentoxy and hexoxy. All alkyl, alkenyl and alkynyl groups shall be understood as being branched or unbranched where structurally possible and unless otherwise specified. Other more specific definitions are as follows:
The term "aroyl" as used in the present specification shall be understood to mean "benzoyl" or "naphthoyl". NMP: l-methyl-2-pyrrolidinone; THF: tetrahydrofuran;
DMF: N,N'-dimethylformamide; DMAC: N-N'-dimethylacetamide; DMSO: dimethylsulfoxide; DMAP: 4-dimethylaminopyridine; DBU: l,8-diazabicyclo[5.4.0]undec-7-ene;
PROCESS FOR MAKING COMPOUNDS OF THE FORMU A The novel process comprises: STEP 1:
Reacting in a suitable solvent an amino-heterocycle NH2-Arj with a haloformate RaOC(X)Ha, wherein Ra represents C2-3 halocarbon, preferably 2,2,2-trichloroethyl, and Ha represents halogen, preferably chloro, X is as defined above, in the presence of a suitable base, to produce carbamate of the formula (II):
Preferable formate RaOC(X)Ha are those, which upon hydrolysis of the formula(II) intermediates, will form a water soluble byproduct which is easily removed by aqueous washing, such byproduct would be, for example, 2,2,2-trichloroethanol. Examples of preferred RaOCOHa are trichloroethyl chloroformate or trichloroethyl chlorothioformate. Accordingly, a preferred compound of the formula(II) is:
Reaction conditions such as the selection of a suitable solvent and temperature is within the skill of the ordinary artisan depending on the particular compounds desired. Typically, the reaction of step 1 is in a non-aqueous or an aqueous solvent, preferably THF or ethyl acetate, in the presence of a suitable base such as tertiary amine for example triethylamine, diisopropylethylamine, N-methylpyrrolidine, DBU(1,8- diazabicyclo[5.4.0]undec-7-ene), DMAP(4-dimethylaminopyridine), N- methylmorpholine, pyridine, methyl pyridine or inorganic bases such as sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate and potassium bicarbonate. Preferred suitable bases for step 1 are diisopropylethylamine, NaOH or N-methylpyrrolidine. The reaction occurs at a temperature of about 0 - 100°C, preferably 5 - 15 °C, for about 0.5 - 24 hrs, preferably 3- 4 hrs.
STEP 2
For certain preferred embodiments, Step 2 proceeds as follows. Reacting a Z-Ar2-MH, where Z is a nitro or nitroso group, M is O, S, or NH, and Ar2 is as defined hereinabove, with a Y-J-Q moiety in a suitable solvent to produce the intermediate of formula (III)
^Ar Q
Z (III)
wherein L and Q are as defined hereinabove , Y is a leaving group such as a halogen and M-J constitutes L;
A suitable solvent for the above reaction would be a polar non-protic organic solvent, such as acetonitrile, DMF (N,N'-dimethylformamide), DMAC (N-N'- dimethylacetamide), DMSO (dimethylsulfoxide) and NMP (l-methyl-2-pyrrolidinone), preferably NMP, at a temperature of about 50 - 100 °C, preferably between 75 - 95 °C, for about 0.5-24 hrs, preferably 3-4 hrs.
For other embodiments of L, analogous methods can be found in U.S. Patent Application Nos. 09/484,638 and 09/505,582 incorporated in their entirety by reference.
STEP 3
Reducing compound of formula (III) with catalytic hydrogenation or non-catalytic reduction to produce the intermediate of formula (IV):
,Ar„ ,Q
H2N' '
(IV)
Catalytic hydrogenation is preferred, a preferred catalyst is Pd C. Reaction conditions such as the selection of a suitable solvent and temperature is within the skill of the ordinary artisan. The catalytic hydrogenation with respect to H2 pressure and time can be varied, a preferable hydrogenation occurs under about 30 psi for about 1 hr - 24 hours.
STEP 4 Reacting the intermediate of formula (II) with the intermediate of formula (IV) with or without base, preferably with a base. A suitable base will be one such as tertiary amine for example triethylamine, diisopropylethylamine, N-methylpyrrolidine, DBU, DMAP, N-methylmorpholine, pyridine, methyl pyridine or an inorganic base such as sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate and potassium bicarbonate. Preferred bases are diisopropylethylamine or N-
methylpyrrolidine. The reaction takes place in the presence of suitable solvent to produce the product of formula (I):
(II) (IV) (I)
Reaction conditions such as the selection of a suitable solvent, base and temperature can be varied according to the specific compound of the formula(I) that is desired. The reaction can be run in a suitable polar, or a suitable non-polar solvent such as methylene chloride or chloroform or in heptane, hexane, cyclohexane, ethyl acetate, benzene, toluene, xylene, tetrahydropfuran, dioxane, ethyl ether, methyl butyl ether or in a biphasic aqueous/organic mixture. Preferably the solvent will be a polar non-protic organic solvent such as NMP(l-methyl-2-pyrrolidinone), acetonitrile, DMF(N,N-dimethylformamide), DMAC(N,N-dimethylacetamide) or DMSO, more preferably DMSO or NMP, which is heated to an appropriate temperature, preferably about 55-60 °C for about 1.5 hours. Particular separation methods depending on the compound desired will be apparent to those of ordinary skill in the art. A preferred method is shown in Example 1 in the present specification.
A preferred subgeneric aspect of the invention comprises a process of producing compounds of the formula(I) wherein Ar2 is naphthyl, tetrahydronaphthyl, indanyl or indenyl.
A more preferred subgeneric aspect of the invention comprises a process of producing compounds of the formula(I) wherein Ar2 is naphthyl.
A yet more preferred subgeneric aspect of the invention comprises a process of producing compounds of the formula (I), as described in the immediate previous paragraph, wherein:
Ari is thiophene or pyrazole; Ar2 is 1 -naphthyl;
L is Cι-6 saturated or unsaturated branched or unbranched carbon chain wherein one or more methylene groups are optionally independently replaced by O,N or S; and wherein said linking group is optionally substituted with 0-2 oxo groups and one or more CM branched or unbranched alkyl optionally substituted by one or more halogen atoms; or L is cyclopentenyl, cyclohexenyl, cycloheptenyl, each optionally substituted with an oxo group or 1-3 CM branched or unbranched alkyl, CMalkoxy or CMalkylamino; or L is phenyl, pyridine, furan or thiophene each being optionally independently substituted with 1-3 CM branched or unbranched alkyl, d-4alkoxy, hydroxy, cyano, mono- or di- (Cι-3 alkyl)amino, Cι-6 alkyl-S(O)q or halogen; wherein said cyclic group is optionally attached to a CM saturated or unsaturated branched or unbranched carbon chain wherein said carbon chain is in turn covalently attached to Q , said carbon chain is optionally partially or fully halogenated and wherein one or more methylene groups are optionally replaced by O, NH, S(O), S(O)2 or S, wherein said methylene groups are further optionally independently substituted with 1-2 oxo groups and one or more C1-4 branched or unbranched alkyl optionally substituted by one or more halogen atoms;
Ri is C3-4alkyl branched or unbranched, cyclopropyl or cyclohexanyl optionally partially or fully halogenated and optionally substituted with one to three Cι-3 alkyl groups;
R3 is selected from the group consisting of CMalkyl branched or unbranched optionally partially or fully halogenated, cyclopentanyl optionally partially or fully halogenated and optionally substituted with one to three Cι-3 alkyl groups, phenyl, pyridinyl each being optionally substituted with one to five groups selected from the group consisting of a Cι-6 branched or unbranched alkyl, phenyl, naphthyl, pyridinyl, Cι-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl Cι-5 alkyl, naphthyl Cι-5 alkyl,
halo, hydroxy, cyano, Cι-3 alkyloxy which may optionally be partially or fully halogenated, phenyloxy, naphthyloxy, pyridinyloxy, nitro, amino, mono- or di-(Cι_ 3)alkylamino, phenylamino, naphthylamino, pyridinylamino, NH2C(O), a mono- or di- (Cι-3)alkyl aminocarbonyl, Cι- alkyl-C(O)-Cι-4 alkyl, amino-Cι-5 alkyl, mono- or di-(Cι_ 3)alkylamino-Cι-5 alkyl, amino-S(O)2, di-(Cι-3)alkylamino-S(O)2, R-i-Ci-salkyl, R5-Cι-5 alkoxy, R6-C(O)-C]-5 alkyl and R7-Cι-5 alkyl-N(R8)-; and R3 is alkoxycarbonylalkyl;
A yet further preferred subgeneric aspect of the invention comprises a process of producing compounds of the formula (I), as described in the immediate previous paragraph, wherein Ari is pyrazole.
A still yet further preferred subgeneric aspect of the invention comprises a process of producing compounds of the formula (I), as described in the immediate previous paragraph, wherein L is Cι-5 saturated carbon chain wherein one or more methylene groups are optionally independently replaced by O,N or S; and wherein said linking group is optionally substituted with 0-2 oxo groups and one or more CM branched or unbranched alkyl optionally substituted by one or more halogen atoms;
More particularly preferred embodiments of the process of the invention is where L is propoxy, ethoxy, methoxy, methyl, propyl, C3-5 acetylene or methylamino each being optionally substituted as described herein and Q is morpholine.
A even more particularly preferred embodiment of L is ethoxy optionally substituted, the base is diisopropylethylamine and the polar non-protic organic solvent is DMSO.
In order that this invention be more fully understood, the following examples are set forth. These examples are for the purpose of illustrating preferred embodiments of this invention, and are not to be construed as limiting the scope of the invention in any way.
SYNTHETIC EXAMPLES
EXAMPLE 1 l-[3-tert-butyl-l-p-tolyl-lH-pyrazol-5-ylJ-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-l- yl]-urea.
(i)
5-Amino-3-ι'-butyl-l-p-tolylpyrazole hydrochlonde: A solution of pivaloylacetonitrile (750 g, 6.0 mol) and ?-tolylhydrazine hydrochloride (660 g, 4.2 mol) in methanol (2.8 L) was refluxed for 3 h. Heptane was added, and methanol was removed by distillation. The product was crystallized from the solution, collected by filtration and dried in vacuum oven to constant weight. Yield: 1.05 kg, 94%. 1H NMR δ (CDC13) 7.50 (d, 2H), 7.30 (d, 2H), 5.60 (s, IH), 2.45 (s, 3H), 1.40 (s, 9H). MS (Cl) m/z 229 (M+ + H).
5-(2,2,2-Trichloroethoxycarbonyl)amino-3-^-butyl-l-p-tolylpyrazole: A mixture of 5- amino-3-t-butyl-l-/?-tolylpyrazole hydrochloride (300 g, 1.13 mol), water (0.9 L), EtOAc (2.1 L) and NaOH (117 g, 2.84 mol) was stirred between 5 -15 °C for 30 min. To this mixture, 2,2,2-trichloroethyl chloroformate (342 g, 1.58 mol) was added over 1 h between 5 - 15 °C. The mixture was stirred at room temperature for 2 h, and then the aqueous layer was separated from the EtOAc layer. The EtO Ac layer was washed with brine (2 x 0.9 L) and dried over MgSO4 (60 g). The EtOAc layer was collected by filtration. To this solution, heptane was added. A part of the solution was removed by distillation. The product was crystallized from the solution, collected by filtration and dried in vacuum oven to constant weight. Yield: 409 g, 90%. Η NMR (CDC13) δ 7.40 (d, 2H), 7.30 (d, 2H), 6.40 (s, IH), 4.80 (s, 2H), 2.40 (s, 3H), 1.40 (s, 9H). MS (El) m/z 404 (M+).
4-Nitro-l-(2-morpholinethoxy)naphthalene: A mixture of 4-nitro-l- hydroxynaphthalene (194 g, 1.0 mol), 4-(2-chloroethyl)moφholine hydrochloride (264 g, 1.4 mol), NaOH (58 g, 1.4 mol), K2CO3 (339 g, 2.4 mol) and l-methyl-2-pyrrolidinone (1.0 L) was heated to 90 - 100 °C and held for 1 - 2 h. The mixture was cooled to 40 °C and water was slowly added. The mixture was cooled to 5 °C and held for 4 h. The product was collected by filtration, washed with water, cyclohexane and dried in vacuum to constant weight. Yield: 227 g, 75%. Η NMR (CDC13) δ 8.76 (d, IH), 8.38 (m, 2H), 7.74 (dd, IH), 7.58 (dd, 1 H), 6.79 (d, 1 H), 4.38 (dd, 2 H), 3.74 (d, 4 H), 2.98 (dd, 2H), 2.65 (d, 4 H). MS (El) m/z 303 (M + 1).
4-Amino-l-(2-morpholinethoxy)naphthalene hydrochloride: A mixture of 4-nitro-l- (2-morpholinethoxy)naphthalene (40 g, 0.13 mol), MeOH (280 mL) and Pd/C (50% water, 1.2 g) was hydrogenated under 30 psi for 24 h. The catalyst was filtered through a layer of diatomaceous earth under nitrogen. To this filtrate 20 mL of HCl (37%) and cyclohexane (200 mL) were added. The solvent was removed under reduced pressure and the product collected by filtration. The product was dried in vacuum to constant weight. Yield: 33 g, 82%. Η NMR (DMSO) δ 8.38 (d, IH), 8.00 (d, IH), 7.72 (dd, IH),
7.64 (m, 2H), 7.05 (d, IH), 4.62 (s, 2H), 4.00 (b, 4H), 3.88 (s, 2H), 3.40 (b, 4H). MS (El) m/z 273 (M+).
l-[3-tert-butyl-l-p-tolyl-lH-pyrazol-5-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-l- ylj-urea: A solution of 5-(2,2,2-trichloroethoxycarbonyl)amino-3-t-butyl-l-p- tolylpyrazole ( 10.6 g, 26 mmol), 4-amino-l-(2-morpholinethoxy)naphthalene (free base from HCl salt above, 7.16 g, 26 mmol), diisopropylethylamine (3.2 g, 25 mmol) and DMSO (75 mL) was heated to 55 - 60 °C and held for 1.5 h. To this solution, ethyl acetate (100 mL) was added. The organic layer was washed with brine (4x50 mL), and dried over MgSO . The solvent was removed under reduced pressure, and residue was crystallized from acetonitrile (50 mL) at 0 °C. The product was collected by filtration, recrystallized from isopropanol and dried in vacuum to constant weight, m.p.: 151-152 °C. Yield: 11.4g, 87%. 1H NMR (DMSO) δ 8.75 (s, IH), 8.51 (s, IH), 8.21 (d, IH), 7.85 (d, IH), 7.65 (d, IH), 7.55 (m, 2H), 7.49 (dd, IH), 7.35 (dd, IH), 6.95 (d, IH), 6.38 (s, IH), 4.26 (dd, 2H), 3.60 (dd, 4H), 2.81 (dd, 2H), 2.55 (dd, 4H), 2.38 (s, 3H), 1.29 (s, 9H). MS (Cl) m/z 528 (M++l).
The following additional non-limiting examples can be made using the novel process of the invention:
EXAMPLE 2
l-[3-tert-butyl-l-p-tolyl-lH-pyrazol-5-yl]-3-{4-[5-(morpholin-4-ylmethyl)fur-2- yljnaphthalen-l-yl} urea:
EXAMPLE 3
l-[3-tert-butyl-l-p-tolyl-lH-pyrazol-5-ylJ-3-{4-[6-(morpholin-4-ylmethyl)pyridin-3- yl]naphthalen-l-yl} urea:
A solution of 5-(2,2,2-trichloroethoxycarbonyl)amino-3-t-butyl-l-p-tolylpyrazole (26 mmol), l-amino-4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalene (26 mmol), diisopropylethylamine ( 25 mmol) and DMSO (75 mL) is heated to 55 - 90°C and held for 2-8 h. To this solution, ethyl acetate (100 mL) is added. The organic layer is washed with brine (4x50 mL), and dried over MgSO . The solvent is removed under reduced pressure, and residue is crystallized from a suitable solvent such as acetonitrile (50 mL) at 0 °C. The product is collected by filtration and recrystallized from a suitable solvent such as isopropanol and dried in vacuum to constant weight.
EXAMPLE 4 l-[3-tert-butyl-l-p-tolyl-lH-pyrazol-5-yl]-3-(4-{6-[(3- methoxypropyl)methylamino]pyridin-3-yl}naphthalen-l-yl)urea
A solution of 5-(2,2,2-trichloroethoxycarbonyl)amino-3-t-butyl-l-p-tolylpyrazole (26 mmol), l-amino-4-{6-[(3-methoxypropyl)methylamino]pyridin-3-yl}naphthalene (26 mmol), diisopropylethylamine ( 25 mmol) and DMSO (75 mL) is heated to 55 - 90°C and held for 2-8 h. To this solution, ethyl acetate (100 mL) is added. The organic layer is washed with brine (4x50 mL), and dried over MgSO . The solvent is removed under reduced pressure, and residue is crystallized from a suitable solvent such as acetonitrile (50 mL) at 0 °C. The product is collected by filtration and recrystallized from a suitable solvent such as isopropanol and dried in vacuum to constant weight.
EXAMPLE 5 l-[3-tert-butyl-l-p-tolyl-lH-pyrazol-5-yl]-3-[4-(3-pyridin-4-yl-propoxy)naphthalen-l- ylj-urea
A solution of 5-(2,2,2-trichloroethoxycarbonyl)amino-3-t-butyl-l-p-tolylpyrazole (26 mmol), l-amino-4-(3-pyridin-4-ylpropoxy)naphthalene (26 mmol), diisopropylethylamine ( 25 mmol) and DMSO (75 mL) is heated to 55 - 90°C and held for 2-8 h. To this solution, ethyl acetate (100 mL) is added. The organic layer is washed with brine (4x50 mL), and dried over MgSO4. The solvent is removed under reduced pressure, and residue is crystallized from a suitable solvent such as acetonitrile (50 mL)
at 0 °C. The product is collected by filtration and recrystallized from a suitable solvent such as isopropanol and dried in vacuum to constant weight.
EXAMPLE 6
l-[3-tert-butyl-l-(2-methylpyridin-5-yl)-lH-pyrazol-5-yl]-3-[4-(pyridin-4-yl- methoxy)naphthalen-l-yl]-urea
A solution of 5-(2,2,2-trichloroethoxycarbonyl)amino-3-t-buryl- 1 -(2-methylpyridin-5- yl)pyrazole (26 mmol), l-amino-4-(pyridin-4-ylmethoxy)naphthalene (26 mmol), diisopropylethylamine ( 25 mmol) and DMSO (75 mL) is heated to 55 - 90°C and held for 2-8 h. To this solution, ethyl acetate (100 mL) is added. The organic layer is washed with brine (4x50 mL), and dried over MgSO4. The solvent is removed under reduced pressure, and residue is crystallized from a suitable solvent such as acetonitrile (50 mL) at 0 °C. The product is collected by filtration and recrystallized from a suitable solvent such as isopropanol and dried in vacuum to constant weight.
EXAMPLE 7 l-[3-tert-butyl-l-p-tolyl-lH-pyrazol-5-yl]-3-[4-(2-pyridin-4-yl- ethenyl)naphthalen-l-yl]-urea
EXAMPLE 8
l-(5-tert-Butyl-2-methyphenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-l-yljurea:
A solution of 5-t-butyl-2-methyl-l-(2,2,2-trichloroethoxycarbonyl)aminobenzene (26 mmol), l-amino-4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalene (26 mmol), diisopropylethylamine (3.2 g, 25 mmol) and DMSO (75 mL) is heated to 55 - 60 °C and held for 1.5 h. To this solution, ethyl acetate (100 mL) is added. The organic layer is washed with brine (4x50 mL), and dried over MgSO4. The solvent is removed under reduced pressure, and residue is crystallized from a suitable solvent such as acetonitrile (50 mL) at 0 °C. The product is collected by filtration and recrystallized from a suitable solvent such as isopropanol and dried in vacuum to constant weight.
Claims
1. A process for producing a compound of the formula (I):
(I) wherein:
Ari is a heterocyclic group selected from the group consisting of phenyl, pyridine, pyridone, pyrrole, pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan and thiophene; wherein Ari is optionally substituted by one or more Rj, R2 or R3;
Ar2 is:
phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl or indole each being optionally substituted with one to three R2 groups;
L, a linking group, is:
Ci-io saturated or unsaturated branched or unbranched carbon chain; wherein one or more methylene groups are optionally independently replaced by O,N or S; and wherein said linking group is optionally substituted with 0-2 oxo groups and one or more CM branched or unbranched alkyl optionally substituted by one or more halogen atoms; or L is a cyclic group which is: a) a C5-8 cycloalkyl or cycloalkenyl optionally substituted with 1-2 oxo groups, 1-3 CM branched or unbranched alkyl, CM alkoxy or CM alkylamino chains; b) phenyl, furan, thiophene, pyrrole, imidazolyl, pyridine, pyrimidine, pyridinone, dihydropyridinone, maleimide, dihydromaleimide, piperdine, piperazine or pyrazine each being optionally independently substituted with 1-3 CM branched or unbranched alkyl, Ci ^alkoxy, hydroxy, cyano, mono- or di-(Cι-3 alkyl)amino, Cι-6 alkyl-S(O)q, or halogen; wherein said cyclic group is optionally attached to a CM saturated or unsaturated branched or unbranched carbon chain wherein said carbon chain is in turn covalently attached to Q , said carbon chain is optionally partially or fully halogenated and wherein one or more methylene groups are optionally replaced by O, NH, S(O), S(O)2 or S, wherein said methylene groups are further optionally independently substituted with 1-2 oxo groups and one or more CM branched or unbranched alkyl optionally substituted by one or more halogen atoms;
Q is selected from the group consisting of:
a) phenyl, naphthyl, pyridine, pyrimidine, pyridazine, imidazole, benzimidazole, furan, thiophene, pyran, naphthyridine, oxazo[4,5-b]pyridine and imidazo[4,5-b]pyridine, which are optionally substituted with one to three groups selected from the group consisting of halogen, Cι-6 alkyl, Cι-6 alkoxy, hydroxy, mono- or di-(Cι-3 alkyl)amino, Cι-6 alkyl-S(O)m and phenylamino wherein the phenyl ring is optionally substituted with one to two groups selected from the group consisting of halogen, Cι-6 alkyl and Cι-6 alkoxy; b) tetrahydropyran, tetrahydrofuran, 1,3-dioxolanone, 1,3-dioxanone, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine sulfoxide, thiomorpholine sulfone, piperidine, piperidinone, tetrahydropyrimidone, cyclohexanone, cyclohexanol, pentamethylene sulfide, pentamethylene sulfoxide, pentamethylene sulfone, tetramethylene sulfide, tetramethylene sulfoxide and tetramethylene sulfone which are optionally substituted with one to three groups selected from the group consisting of Cι-6 alkyl, Cι-6 alkoxy, hydroxy, mono- or di-(Cι-3 alkyl)amino-Cι-3 alkyl, phenylamino-Cι-3 alkyl and Cι-3 alkoxy-Cι-3 alkyl; c) Cι-6 alkoxy, secondary or tertiary amine wherein the amino nitrogen is covalently bonded to groups selected from the group consisting of Cι-3 alkyl and Cι-5 alkoxyalkyl and phenyl wherein the phenyl ring is optionally substituted with one to two groups selected from the group consisting of halogen, Cι-6 alkoxy, hydroxy or mono- or di- (d-3 alkyl)amino, C1-6 alkyl-S(O)r and phenyl-S(O),, wherein the phenyl ring is optionally substituted with one to two groups consisting of halogen, d-6 alkoxy, hydroxy and mono- or di-(d-3 alkyl)amino;
Ri is selected from the group consisting of:
a) C3-ιo branched or unbranched alkyl, which may optionally be partially or fully halogenated, and optionally substituted with one to three phenyl, naphthyl or heterocyclic groups selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl; each such phenyl, naphthyl or heterocycle selected from the group hereinabove described, being substituted with 0 to 5 groups selected from the group consisting of halogen, Cι-6 branched or unbranched alkyl which is optionally partially or fully halogenated, C3-8 cycloalkyl, C5.8 cycloalkenyl, hydroxy, cyano, Cι-3 alkyloxy which is optionally partially or fully halogenated, NH2C(O) and di(Cι- )alkylaminocarbonyl; b) C3- cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, which are optionally partially or fully halogenated and optionally substituted with one to three Cι-3 alkyl groups, or an analog of such cycloalkyl group wherein one to three ring methylene groups are replaced by groups independently selected from O, S, CHOH, >C=O, >C=S and NH; c) C3-ιo branched alkenyl which may optionally be partially or fully halogenated, and which optionally be substituted with one to three Cι-5 branched or unbranched alkyl, phenyl, naphthyl or heterocyclic groups, with each such heterocyclic group being independently selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, and each such phenyl, naphthyl or heterocyclic group being substituted with 0 to 5 groups selected from halogen, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, hydroxy, cyano, Cι-3 alkyloxy which is optionally partially or fully halogenated, NH2C(O) and mono- or di(Cι-3)alkylaminocarbonyl; d) C - cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein such cycloalkenyl group is optionally be substituted with one to three Cι-3 alkyl groups; e) cyano; and, f) methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl;
R2 is selected from the group consisting of:
a Ci-6 branched or unbranched alkyl optionally partially or fully halogenated, acetyl, aroyl, CM branched or unbranched alkoxy optionally partially or fully halogenated, halogen, methoxycarbonyl and phenylsulfonyl;
R3 is selected from the group consisting of:
a) a phenyl, naphthyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl and indazolyl wherein such phenyl, naphthyl or heterocyclic group is optionally substituted with one to five groups selected from the group consisting of a Cι-6 branched or unbranched alkyl, phenyl, naphthyl, heterocycle selected from the group hereinabove described, Cι-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl Cι-5 alkyl, naphthyl C alkyl, halo, hydroxy, cyano, Cι-3 alkyloxy which may optionally be partially or fully halogenated, phenyloxy, naphthyloxy, heteraryloxy wherein the heterocyclic moiety is selected from the group hereinabove described, nitro, amino, mono- or di-(Cι-3)alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described, NH2C(O), a mono- or di-(Cι-3)alkyl aminocarbonyl, Cι-5 alkyl-C(O)-CM alkyl, amino-Cι-5 alkyl, mono- or di-(Cι-
3)alkylamino-Cι-5 alkyl, amino-S(O)2, di-(C]-3)alkylamino-S(O)2, R-rd-salkyl, R5-C1- 5 alkoxy, R6-C(O)-Cι,5 alkyl and R7-C1.5 alkyl-N(Rs)-; b) a fused aryl selected from the group consisting of benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heterocyclyl selected from cyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinoline, cyclohexanoquinoline, cyclopentanoisoquinoline, cyclohexanoisoquinoline, cyclopentanoindole, cyclohexanoindole, cyclopentanobenzimidazole, cyclohexanobenzimidazole, cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; wherein the fused aryl or fused heterocyclyl ring is substituted with 0 to 3 groups independently selected from phenyl, naphthyl, heterocyclyl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, and isothiazolyl, Cι-6 branched or unbranched alkyl which is optionally partially or fully halogenated, halo, cyano, Cι-3 alkyloxy which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy wherein the heterocyclyl moiety is selected from the group hereinabove described, nitro, amino, mono- or di-(Cι-3)alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described, NH2C(O), a mono- or di-(Cι-3)alkyl aminocarbonyl, CM alkyl-OC(O), Cι-5 alkyl-C(O)-CM branched or unbranched alkyl, an amino-Cι.5 alkyl, mono- or di-(Cι-3)alkylamino-C!-5 alkyl, Rcι-Cι-5 alkyl, Rι0-Cι.5 alkoxy, Rn - C(O)-d-5 alkyl and R,2 -Cι-5 alkyl-N(R)3)-; c) cycloalkyl selected from the group consisting of cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, wherein the cycloalkyl is optionally partially or fully halogenated and optionally substituted with one to three Cι-3 alkyl groups;
d) C5- cycloalkenyl, selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one to three Cι-3 alkyl groups;
e) acetyl, aroyl, alkoxycarbonylalkyl and phenylsulfonyl; and
f) Cι-6 branched or unbranched alkyl optionally partially or fully halogenated;
Ri and R2 taken together optionally form a fused phenyl or pyridinyl ring;
each R8 and R]3 is independently selected from the group consisting of:
hydrogen and CM branched or unbranched alkyl optionally partially or fully halogenated;
each R4, R5, Rs, R , R9, Rio, Rn and Rι2 is independently selected from the group consisting of: morpholine, piperidine, piperazine, imidazole and tetrazole;
m is 0, 1 or 2;
r is 0, 1 or 2;
q is 0, 1 or 2;
t is 0, 1 or 2; and X is O or S;
said process comprising: reacting of intermediate of formula (II) with intermediate of formula (IV) in the presence of a suitable base said reaction taking place in a suitable solvent at a suitable temperature for a reaction time of about 1.5 hours:
2. The process according to claim 1 wherein Ra is 2,2,2-trichloroethyl; the organic solvent is a polar non-protic solvent selected from the group consisting of NMP, acetonitrile, DMF, DMAC and DMSO; the base is selected from the group consisting of triethylamine, diisopropylethylamine, N-methylpyrrolidine, DBU, DMAP, N-methylmorpholine, pyridine, methyl pyridine and an inorganic base; the temperature is about 55-60°C;
Ar is selected from the group consisting of naphthyl, tetrahydronaphthyl, indanyl and indenyl, and X is O.
3. The process according to claim 2 wherein An is naphthyl; the polar non-protic organic solvent is selected from the group consisting of NMP and DMSO; and the base is selected from the group consisting of diisopropylethylamine and N- methylpy rrolidine .
4. The process according to claim 3 wherein
Ari is thiophene or pyrazole;
Ar2 is 1 -naphthyl;
L is Cι-6 saturated or unsaturated branched or unbranched carbon chain wherein one or more methylene groups are optionally independently replaced by
O,N or S; and wherein said linking group is optionally substituted with 0-2 oxo groups and one or more CM branched or unbranched alkyl optionally substituted by one or more halogen atoms; or L is cyclopentenyl, cyclohexenyl or cycloheptenyl each optionally substituted with an oxo group or 1-3 C branched or unbranched alkyl, Cι- alkoxy or CMalkylamino; or L is phenyl, pyridine, furan or thiophene each being optionally independently substituted with 1-3 CM branched or unbranched alkyl, CMalkoxy, hydroxy, cyano, mono- or di- (Cι-3 alkyl)amino, Cι-6 alkyl-S(O)q or halogen; wherein said cyclic group is optionally attached to a CM saturated or unsaturated branched or unbranched carbon chain wherein said carbon chain is in turn covalently attached to Q , said carbon chain is optionally partially or fully halogenated and wherein one or more methylene groups are optionally replaced by O, NH, S(O), S(O)2 or S, wherein said methylene groups are further optionally independently substituted with 1-2 oxo groups and one or more CM branched or unbranched alkyl optionally substituted by one or more halogen atoms;
Ri is d^alkyl branched or unbranched, cyclopropyl or cyclohexanyl optionally partially or fully halogenated and optionally substituted with one to three Cι-3 alkyl groups; R3 is selected from the group consisting of CMalkyl branched or unbranched optionally partially or fully halogenated; cyclopentanyl optionally partially or fully halogenated and optionally substituted with one to three Cι-3 alkyl groups; phenyl, pyridinyl each being optionally substituted with one to five groups selected from the group consisting of a Cι-6 branched or unbranched alkyl, phenyl, naphthyl, pyridinyl, Cι-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl Cι-5 alkyl, naphthyl Cι-5 alkyl, halo, hydroxy, cyano, Cι-3 alkyloxy which may optionally be partially or fully halogenated, phenyloxy, naphthyloxy, pyridinyloxy, nitro, amino, mono- or di-(d. 3)alkylamino, phenylamino, naphthylamino, pyridinylamino, NH2C(O), a mono- or di-
(Cι-3)alkyl aminocarbonyl, Cι-5 alkyl-C(O)-CM alkyl, amino-Ci-5 alkyl, mono- or di-(d.
3)alkylamino-Cι-5 alkyl, amino-S(O)2, di-(Cι-3)alkylamino-S(O)2, Rj-Ci-salkyl, R5-Cι-5 alkoxy, R6-C(O)-Cι-5 alkyl and R7-Cι-5 alkyl-N(Rs)-; and R3 is alkoxycarbonylalkyl;
5. The process according to claim 4 wherein Ari is pyrazole.
6. The process according to claim 5 wherein L is Cι-5 saturated carbon chain wherein one or more methylene groups are optionally independently replaced by O,N or S; and wherein said linking group is optionally substituted with 0-2 oxo groups and one or more CM branched or unbranched alkyl optionally substituted by one or more halogen atoms.
7. The process according to claim 5 wherein
L is propoxy, ethoxy, methoxy, methyl, propyl, C -5 acetylene or methylamino each optionally substituted with 0-2 oxo groups and one or more CM branched or unbranched alkyl optionally substituted by one or more halogen atoms; and
Q is morpholine.
7. The process according to claim 6 wherein L is propoxy, ethoxy or methoxy.
8. The process according to claim 7 wherein L is ethoxy, the base is diisopropylethylamine and the polar non-protic organic solvent is DMSO.
9. A process of producing an intermediate compound of the formula(II)
compπsing: reacting an aminoheterocycle NH2- Ari with with a formate RaOC(X)Ha, in a suitable solvent in the presence of a suitable base at about 0 to 100°C for about 0.5 to 24 hours, wherein
Ra represents C2-3 halocarbon, and Ha represents halogen, X and Ari are as defined in claim 1, to produce carbamate of the formula (II).
10. The process according to claim 9 wherein Ra is 2,2,2-trichloroethyl, Ha is chloro,
X is O, the solvent is THF or ethyl acetate, the base is selected from the group consisting diisopropylethylamine, N- methylpyrrolidine and NaOH; the temperature is about 5 to 15°C; and the time is about 3 hours.
11. A carbamate compound of formula:
wherein Ari is thiophene or pyrazole and X is O.
12. The carbamate compound according to claim 11 wherein Ari is l-tolyl-3-t-butyl-pyrazole-5-yl.
13. A process for producing an intermediate compound of the formula (III)
compnsmg: reacting a Z-Ar2-MH compound with a Y-J-Q moiety in a polar non-protic organic solvent at a temperature of about 50-100°C to produce the intermediate with formula (III); wherein Z is a nitro or nitroso group, M is O, S, or NH, Y is a leaving group, M-J constitutes L; and wherein Ar2ι L and Q are as defined in claim 1.
14. The process according to claim 13 wherein the solvent is selected from the group consisting of acetonitrile, DMF, DMAC, DMSO and NMP and the temperature is about
75-95°C.
15. An intermediate compound of the formula(III):
,Ar„ .Q
(III)
wherein Z is nitro or nitroso and wherein
Ar2 is 1 -naphthyl,
L is propoxy, ethoxy, methoxy, methyl, propyl, C3-5 acetylene or methylamino, and Q is morpholine.
16. A process of producing an intermediate compound of formula (IV):
^Ar Q
H2N L
(IV) comprising: reducing compound of formula (III) by catalytic hydrogenation with a Pd/C catalyst under about 30 psi for about 1-24 h:
wherein Z,An,L and Q are as defined above in claim 13, to produce the intermediate of formula (IV).
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE60024830T DE60024830T2 (en) | 1999-07-09 | 2000-06-27 | METHOD FOR PRODUCING HETEROARYL SUBSTITUTED UREA BONDING |
| CA002374737A CA2374737C (en) | 1999-07-09 | 2000-06-27 | Novel process for synthesis of heteroaryl-substituted urea compounds |
| JP2001509725A JP4162406B2 (en) | 1999-07-09 | 2000-06-27 | Novel synthesis method of heteroaryl-substituted urea compounds |
| MXPA02000314A MXPA02000314A (en) | 1999-07-09 | 2000-06-27 | Novel process for synthesis of heteroaryl-substituted urea compounds. |
| EP00941745A EP1200411B1 (en) | 1999-07-09 | 2000-06-27 | Process for synthesis of heteroaryl-substituted urea compounds |
| AT00941745T ATE312823T1 (en) | 1999-07-09 | 2000-06-27 | METHOD FOR PRODUCING HETEROARYL-SUBSTITUTED UREA COMPOUNDS |
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|---|---|---|---|
| US14309499P | 1999-07-09 | 1999-07-09 | |
| US60/143,094 | 1999-07-09 |
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| WO2001004115A2 true WO2001004115A2 (en) | 2001-01-18 |
| WO2001004115A3 WO2001004115A3 (en) | 2001-09-27 |
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| PCT/US2000/017655 WO2001004115A2 (en) | 1999-07-09 | 2000-06-27 | Novel process for synthesis of heteroaryl-substituted urea compounds |
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| Country | Link |
|---|---|
| US (5) | US6583282B1 (en) |
| EP (1) | EP1200411B1 (en) |
| JP (1) | JP4162406B2 (en) |
| AT (1) | ATE312823T1 (en) |
| CA (1) | CA2374737C (en) |
| DE (1) | DE60024830T2 (en) |
| ES (1) | ES2253233T3 (en) |
| MX (1) | MXPA02000314A (en) |
| WO (1) | WO2001004115A2 (en) |
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Families Citing this family (25)
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| US7989455B2 (en) * | 2005-12-19 | 2011-08-02 | Cytokinetics, Inc. | Compounds, compositions and methods |
| SI1981851T1 (en) * | 2006-01-31 | 2012-05-31 | Array Biopharma Inc | Kinase inhibitors and methods of use thereof |
| EP2865381A1 (en) | 2006-05-18 | 2015-04-29 | Pharmacyclics, Inc. | ITK inhibitors for treating blood cell malignancies |
| BRPI1004176A2 (en) * | 2010-10-25 | 2015-08-11 | Univ Rio De Janeiro | Functionalized aryl and / or heteroaryl urea compounds; synthesis process of these compounds; pharmaceutical composition containing such compounds and uses |
| CN109053623B (en) * | 2018-08-27 | 2020-08-04 | 济南悟通生物科技有限公司 | Preparation method of 4-methyl-5-thiazole formaldehyde |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3291808A (en) * | 1961-08-14 | 1966-12-13 | Parke Davis & Co | Naphthalene diamine compounds and methods for their production |
| US4447624A (en) * | 1980-08-27 | 1984-05-08 | Eastman Kodak Company | Preparation of thiophenes |
| WO2000043384A1 (en) * | 1999-01-19 | 2000-07-27 | Boehringer Ingelheim Pharmaceuticals, Inc. | Aromatic heterocyclic compounds as antiinflammatory agents |
Family Cites Families (51)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US447624A (en) * | 1891-03-03 | Corn-harvester | ||
| US4105766A (en) * | 1977-08-19 | 1978-08-08 | Sterling Drug Inc. | 4,5-Dihydro-5-oxopyrazolo[1,5-a]quinazoline-3-carboxylic acid derivatives |
| HU185294B (en) | 1980-12-29 | 1984-12-28 | Chinoin Gyogyszer Es Vegyeszet | Process for producing substituted urea derivatives |
| US4436567A (en) * | 1982-03-22 | 1984-03-13 | Weikert Roy J | Method for joining webs of aseptic pouches |
| JPS61228444A (en) | 1985-04-02 | 1986-10-11 | Fuji Photo Film Co Ltd | Silver halide color photographic sensitive material |
| EP0272866A1 (en) | 1986-12-23 | 1988-06-29 | Merck & Co. Inc. | 1,4-Benzodiazepines with 5-membered heterocyclic rings |
| GB8908869D0 (en) | 1989-04-19 | 1989-06-07 | Shell Int Research | A process for the preparation of aromatic ureas |
| WO1991004027A1 (en) | 1989-09-15 | 1991-04-04 | Pfizer Inc. | New n-aryl and n-heteroarylamide and urea derivatives as inhibitors of acyl coenzyme a: cholesterol acyl transferase (acat) |
| DD293352A5 (en) | 1990-04-06 | 1991-08-29 | Adw,Zi Fuer Organische Chemie,De | PROCESS FOR PREPARING 2,2-DISUBSTITUTED 1-ACYL AND / OR 9-ACYL-2,3-DIHYDRO-IMIDAZO / 1,2-A / BENZIMIDAZOLE-3-ONEN |
| US5162360A (en) * | 1991-06-24 | 1992-11-10 | Warner-Lambert Company | 2-heteroatom containing urea and thiourea ACAT inhibitors |
| IL104369A0 (en) * | 1992-01-13 | 1993-05-13 | Smithkline Beecham Corp | Novel compounds and compositions |
| BR9306421A (en) | 1992-05-28 | 1998-09-15 | Pfizer | New n-aryl and n-heteroarylurea derivatives as acylcoenzyme a inhibitors: cholesterol acyltransferase (acat) |
| US5342942A (en) | 1992-06-09 | 1994-08-30 | Warner-Lambert Company | Pyrazoloquinazolone derivatives as neurotrophic agents |
| GB9302275D0 (en) | 1993-02-05 | 1993-03-24 | Smithkline Beecham Plc | Novel compounds |
| WO1994022872A1 (en) | 1993-03-30 | 1994-10-13 | Yoshitomi Pharmaceutical Industries, Ltd. | Cell adhesion inhibitor and thienotriazolodiazepine compound |
| US5869043A (en) * | 1993-09-17 | 1999-02-09 | Smithkline Beecham Corporation | Drug binding protein |
| ES2140561T3 (en) * | 1993-09-17 | 2000-03-01 | Smithkline Beecham Corp | DRUG UNION PROTEIN. |
| US5783664A (en) * | 1993-09-17 | 1998-07-21 | Smithkline Beecham Corporation | Cytokine suppressive anit-inflammatory drug binding proteins |
| EP0809492A4 (en) | 1995-02-17 | 2007-01-24 | Smithkline Beecham Corp | Il-8 receptor antagonists |
| IL118544A (en) | 1995-06-07 | 2001-08-08 | Smithkline Beecham Corp | Imidazole derivatives, process for their preparation and pharmaceutical compositions comprising them |
| US5739143A (en) * | 1995-06-07 | 1998-04-14 | Smithkline Beecham Corporation | Imidazole compounds and compositions |
| JPH11514651A (en) | 1995-10-31 | 1999-12-14 | メルク エンド カンパニー インコーポレーテッド | Substituted pyridylpyrroles, compositions containing said compounds and methods of use |
| US6074862A (en) | 1995-12-20 | 2000-06-13 | Signal Pharmaceuticals Inc. | Mitogen-activated protein kinase kinase MEK6 and variants thereof |
| WO1997033883A1 (en) | 1996-03-13 | 1997-09-18 | Smithkline Beecham Corporation | Novel pyrimidine compounds useful in treating cytokine mediated diseases |
| JP2000507558A (en) | 1996-03-25 | 2000-06-20 | スミスクライン・ビーチャム・コーポレイション | Novel treatment for CNS injury |
| EP0889887A4 (en) | 1996-03-25 | 2003-06-11 | Smithkline Beecham Corp | Novel treatment for cns injuries |
| US5948885A (en) * | 1996-05-20 | 1999-09-07 | Signal Pharmaceuticals, Inc. | Mitogen-activated protein kinase p38-2 and methods of use therefor |
| AU736316B2 (en) | 1996-05-20 | 2001-07-26 | Signal Pharmaceuticals, Inc. | Mitogen-activated protein kinase p38-2 and methods of use therefor |
| ES2239357T3 (en) * | 1996-06-10 | 2005-09-16 | MERCK & CO., INC. | REPLACED IMIDAZOLS THAT HAVE INHIBITING ACTIVITY OF CYTOKINS. |
| EP2223920A3 (en) | 1996-06-19 | 2011-09-28 | Aventis Pharma Limited | Substituted azabicyclic compounds |
| EP0956018A4 (en) | 1996-08-21 | 2000-01-12 | Smithkline Beecham Corp | Imidazole compounds, compositions and use |
| WO1998015618A1 (en) | 1996-10-09 | 1998-04-16 | Medical Research Council | Map kinases: polypeptides, polynucleotides and uses thereof |
| CA2273102A1 (en) | 1996-12-03 | 1998-06-11 | Banyu Pharmaceutical Co., Ltd. | Urea derivatives |
| US6147080A (en) | 1996-12-18 | 2000-11-14 | Vertex Pharmaceuticals Incorporated | Inhibitors of p38 |
| US6376214B1 (en) | 1997-02-18 | 2002-04-23 | Smithkline Beecham Corporation | DNA encoding a novel homolog of CSBP/p38 MAP kinase |
| WO1998052558A1 (en) | 1997-05-23 | 1998-11-26 | Bayer Corporation | INHIBITION OF p38 KINASE ACTIVITY BY ARYL UREAS |
| JP2002500650A (en) | 1997-05-23 | 2002-01-08 | バイエル、コーポレイション | RAF kinase inhibitor |
| US6093742A (en) | 1997-06-27 | 2000-07-25 | Vertex Pharmaceuticals, Inc. | Inhibitors of p38 |
| US5851812A (en) * | 1997-07-01 | 1998-12-22 | Tularik Inc. | IKK-β proteins, nucleic acids and methods |
| US5858041A (en) * | 1997-08-22 | 1999-01-12 | David Luetkemeyer | Clean air system |
| CA2223075A1 (en) | 1997-12-02 | 1999-06-02 | Smithkline Beecham Corporation | Drug binding protein |
| CA2315717C (en) | 1997-12-22 | 2011-02-01 | Bayer Corporation | Inhibition of raf kinase using substituted heterocyclic ureas |
| MXPA00006233A (en) | 1997-12-22 | 2002-09-18 | Bayer Ag | INHIBITION OF p38 KINASE ACTIVITY USING SUBSTITUTED HETEROCYCLIC UREAS. |
| IL136768A0 (en) | 1997-12-22 | 2001-06-14 | Bayer Ag | INHIBITION OF p38 KINASE ACTIVITY USING ARYL AND HETEROARYL SUBSTITUTED HETEROCYCLIC UREAS |
| CN1117081C (en) | 1997-12-22 | 2003-08-06 | 拜尔有限公司 | Inhibition of raf kinase using aryl and hetroaryl substituted heterocyclic ureas |
| AU1939999A (en) | 1997-12-22 | 1999-07-12 | Bayer Corporation | Inhibition of p38 kinase using symmetrical and unsymmetrical diphenyl ureas |
| AU2713799A (en) | 1998-03-12 | 1999-09-27 | Novo Nordisk A/S | Modulators of protein tyrosine phosphatases (ptpases) |
| WO2000050425A1 (en) * | 1999-02-22 | 2000-08-31 | Boehringer Ingelheim Pharmaceuticals, Inc. | Polycyclo heterocyclic derivatives as antiinflammatory agents |
| ATE309237T1 (en) | 1999-03-12 | 2005-11-15 | Boehringer Ingelheim Pharma | AROMATIC HETEROCYCLIC COMPOUNDS AS ANTI-INFLAMMATORY ACTIVES |
| NZ528846A (en) | 1999-03-12 | 2005-05-27 | Boehringer Ingelheim Pharma | Compounds useful as anti-inflammatory agents |
| WO2001004115A2 (en) * | 1999-07-09 | 2001-01-18 | Boehringer Ingelheim Pharmaceuticals, Inc. | Novel process for synthesis of heteroaryl-substituted urea compounds |
-
2000
- 2000-06-27 WO PCT/US2000/017655 patent/WO2001004115A2/en active IP Right Grant
- 2000-06-27 CA CA002374737A patent/CA2374737C/en not_active Expired - Lifetime
- 2000-06-27 MX MXPA02000314A patent/MXPA02000314A/en active IP Right Grant
- 2000-06-27 EP EP00941745A patent/EP1200411B1/en not_active Expired - Lifetime
- 2000-06-27 JP JP2001509725A patent/JP4162406B2/en not_active Expired - Lifetime
- 2000-06-27 DE DE60024830T patent/DE60024830T2/en not_active Expired - Lifetime
- 2000-06-27 AT AT00941745T patent/ATE312823T1/en active
- 2000-06-27 ES ES00941745T patent/ES2253233T3/en not_active Expired - Lifetime
- 2000-07-06 US US09/611,109 patent/US6583282B1/en not_active Expired - Lifetime
-
2002
- 2002-11-20 US US10/300,448 patent/US6753426B2/en not_active Expired - Lifetime
-
2003
- 2003-02-10 US US10/361,719 patent/US6774233B2/en not_active Expired - Lifetime
- 2003-02-10 US US10/361,440 patent/US6894173B2/en not_active Expired - Lifetime
- 2003-02-10 US US10/361,731 patent/US6835832B2/en not_active Expired - Lifetime
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3291808A (en) * | 1961-08-14 | 1966-12-13 | Parke Davis & Co | Naphthalene diamine compounds and methods for their production |
| US4447624A (en) * | 1980-08-27 | 1984-05-08 | Eastman Kodak Company | Preparation of thiophenes |
| WO2000043384A1 (en) * | 1999-01-19 | 2000-07-27 | Boehringer Ingelheim Pharmaceuticals, Inc. | Aromatic heterocyclic compounds as antiinflammatory agents |
Non-Patent Citations (1)
| Title |
|---|
| CHONG ET AL.: "Multilevel Selectivity in the mild and high-yielding Chlorosilane-induced Cleavage of Carbamates to Isocyanates" J. ORG. CHEM., vol. 63, 1998, pages 8515-21, XP002155506 * |
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Also Published As
| Publication number | Publication date |
|---|---|
| JP4162406B2 (en) | 2008-10-08 |
| US20030166930A1 (en) | 2003-09-04 |
| CA2374737A1 (en) | 2001-01-18 |
| US20030166931A1 (en) | 2003-09-04 |
| EP1200411A2 (en) | 2002-05-02 |
| US6894173B2 (en) | 2005-05-17 |
| US20030181718A1 (en) | 2003-09-25 |
| ATE312823T1 (en) | 2005-12-15 |
| US6774233B2 (en) | 2004-08-10 |
| US6753426B2 (en) | 2004-06-22 |
| EP1200411B1 (en) | 2005-12-14 |
| JP2003504366A (en) | 2003-02-04 |
| CA2374737C (en) | 2008-02-12 |
| US6583282B1 (en) | 2003-06-24 |
| DE60024830T2 (en) | 2006-06-14 |
| DE60024830D1 (en) | 2006-01-19 |
| US6835832B2 (en) | 2004-12-28 |
| ES2253233T3 (en) | 2006-06-01 |
| MXPA02000314A (en) | 2004-06-22 |
| US20030109703A1 (en) | 2003-06-12 |
| WO2001004115A3 (en) | 2001-09-27 |
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